21-substituted 17-aza-steroids and salts thereof

ABSTRACT

THIS INVENTION RELATES TO 21-SUBSTITUED 17-AZA-STEROIDS AND SALTS THEREOF HAVING THE FORMULA 1   1-(X-CH2-CO-),5A-F,6-E,7-C,7-D,8-B,9-A,9A-G-PERHYDRO-1H-   NAPHTH(1,2-E)INDOLE   WHEREIN A AND B EACH REPRESENT HYDROGEN, C IS HYDROXY GROUP, ESTER OR ETHER, D, E AND F EACH REPRESENT HYDROGEN ATOM, G IS A METHYL GROUP IF THE COMPOUNDS ARE OF ANDROSTANE TYPE,OR A AND B, D AND E AND F AND G EACH REPRESENT TERMINI OF DOUBLE BOND, OR C AND D REPRESENT TOGETHER AN OXO-GROUP, ESPECIALLY A KETAL GROUP, AND X REPRESENTS CHLORINE, BROMINE, HYDROXY OR ACYLOXY A SUBSTITUTED, SECONDARY OR TERTIARY AMINO.

United States Patent 3,790,574 ZI-SUBSTITUTED 17-AZA-STEROIDS AND SALTS THEREOF Zoltn Tuba and Maria Bor, uee Szab, Budapest, Hungary, assignors to Richter Gedeon Vegyeszeti Gyar R.T., Budapest, Hungary No Drawing. Filed June 14, 1971, Ser. No. 152,970 Claims priority, applicationsgl-gungary, June 18, 1970,

Int. Cl. C07d 51/70 US. Cl. 260-268 PC 6 Claims ABSTRACT OF THE DISCLOSURE This invention relates to 2l-substituted l7-aza-steroids and salts thereof having the Formula I CHz-X :0 I N A Y G wherein This invention relates to 2.1-substituted 17-aza-steroids and salts thereof having the Formula I CHz-X wherein A and B each represent hydrogen,

C is a hydroxy group or a protected hydroxy group such as an ester or ether group,

D, E and F each represent hydrogen,

G is a methyl group if the compounds are of androstane A and B, D and E and F and G each represent thermini of a repective double bond, or

C and D represent together an oxo-group or a protected oxo-group, such as a ketal group, and

X represents chlorine, bromine, hydroxy or acyloxy group or a substituted, secondary or tertiary amino group. The compounds of the invention possess valuable pharmacological properties. Among the compounds of the general Formula I are 3,20-dioXo-2l-chloro-17-aza-5aandrostane, 3,20-dioxo-2l-hydroxy-l7-aza-5a-androstane- 21 acetate, 3,20-dioxo-2l-hydroxy-l7-aza-5u-androstane, 3,20-dioxo-2-hydroxy-l7-aza-Su-andstrone 21 hemisuccinate, 3,8 hydroxy 20 oxo-21-chloro-17-aza-5aandrostane, 35,21 dihydroxy 20 0X0 17 aZa-Saandrostane-Zl-acetate and 313,2l-dihydroxy-20-oxo-7-aza- 5a-androstane. These compounds possess a catatoxic activity inducing the oxidaze system of mixed function bound to the microszmes of liver, of about the same order as spironolactone. These compounds can also be used for the treatment of disorders accompanied by endrogeneous corticoid overproduction, similarly to 1- [2- chlorophenyl-(1)-4-chlorophenyl] 2,2 dichloroethane, as well as for the treatment of icterus gr. neonatorum.

21 pyridinium 20 oxo 17 aza-estra-1,3,5(10)- triene-3-methylether iodide, 2l-triethylamonium-ZOmxo- 17-aza-estra-l,3,5(l0)-triene 3 methylether iodide and other compounds of related structure of Formula I possess a curate-like activity less expressed than that of curare. Y

Compounds of the above type may be generally described by the formula:

wherein X is chloro, pyridino, triethylamino, N -methylpiperazinyl, hydroxyl or acetate and the iodide salts thereof.

21-N-(N'-methyl piperazinyl) 20 oxo 17 azaestra1,3,5(l0)-triene-3-methylether, 3 ethylene-dioxy- 20-oxo-2l-N-(N-methyl piperazinyl) l7 aza 51xandrostane and other compounds of related structure of Formula I possess bacteriostatic activity in a concentration of 1 to 5 mg./kg. These compounds exert also a serum cholesterol lowering effect on rats 'When added orally in a dose of 8 to 14 mg./kg. body weight, preferably in a dose of 12 rug/kg. body weight.

Those compounds of the Formula I having an aromatic A-ring do not possess hormonal activities characteristic of estrone derivatives.

According to the invention, compounds are provided which contain a pregnene side chain having a halogen, hydroxy, acyloxy or amino substituent in the 21 position attached to the nitrogen atom in the 17 position. 17-azasteroides of this type have not been described in the literature.

A further object of the invention is to provide a process for the preparation of the compounds having the formula I.

According to the invention the new 2l-substituted-17- aza-steroids of the Formula I are prepared by acylating a compound of the Formula II below-wherein A, B, C, D, E, F, G, AB, DE, PG and CD have the same meanings as stated abovewith a compound of the Formula III,

wherein X and Y each represent a chlorine or bromine atom, according to the Schotten-Baumann method, and optionally subjecting the thus-obtained 17-aza-20-oxo-21- are prepared from 3 substituted 16,17-dioxo-6-oximino- Sa-androstane or 3 substituted 16,17-dioxo-l6-oximinoestra-1,3,5(l)-triene derivatives (US. Pat. No. 3,135,- 772, German Pat. No. 875,650) as follows: The starting l6,l7-dioxo-16-oximino-androstane or estrane derivative is dissolved in glacial acetic acid at a temperature below the boiling point of the solvent, and a mineral acid, preferably sulfuric acid is added to the homogeneous solution. The reaction mixture is kept for several hours at a temperature of 20 to 100 C. depending on the thermal stability of the corresponding oxime derivative, thereafter the glacial acetic acid solution of the product is added dropwise into water. The separated l6,17-seco-l6,l7-dicarboxylic acid-Su-andrOstane or estrane-imide derivative is filtered olf, washed and dried.

The above compounds can also be prepared by subjecting the corresponding 16,17 seco-l6-carbamoyl-17- carbomethoxy-androstane or estrane derivatives to ring closure in an alkaline medium.

The 16,17-seco-16,l7-dicarboxylic imide obtained in the previous step is dissolved in a polar solvent and methanolic bromine solution or sodium hypochlorite solution, as well as an alkali alkoxide solution, preferably sodium methoxide solution are added simultaneously to the reaction mixture. The reaction mixture is stirred initially at room temperature, and stirring is continued at the boiling point of the solution. After about 30 minutes of stirring the solvent is distilled off, the residue is triturated with water, the product is filtered 01f, dried and recrystallized. In this step the corresponding 16 oxo-17-aza-5a-androstane or estrane derivatives are formed. These compounds of lactam structure can also be prepared from the corresponding 16,17 seco-17-carbamoyl-l6-carbomethoxy-5a-androstane or estrane derivatives. According to this latter method the starting substance is dissolved preferably in methanol and treated with lead tetraacetate at the boiling point of the mixture. The lead salts are separated, and the obtained product is converted to the corresponding l'6-oxo- 17-aza-5a-androstane or estrane derivatives by alkaline hydrolysis.

The above-mentioned 16,17-sew 16 carbamoyl-l7- carbomethoxy-derivatives can also be converted to the lactam derivatives under the conditions of the Hofimanndegradation.

The compounds prepared in the second step-Le. the lactam derivativescan be converted to the compounds of the general Formula II by reduction with a complex metal hydride. The starting l6-oxo-l7-aza-5-androstane or estraue derivative is dissolved in an ether solvent, e.g. in tetrahydrofurane or dioxane, or in an aromatic solvent, e.g. in benzene, or toluene, and is treated with lithium aluminumhydride or with a benzene solution of sodiumbis-2-methoxy-ethoxy-aluminumhydride.

The reaction mixture is preferably boiled for several hours under a nitrogen atmosphere, thereafter the excess of the reducing agent is decomposed by conventional methods, the separated gelatinous precipitate of lithium and aluminum hydroxides is filtered off and thoroughly washed. The combined filtrate and wash is evaporated and the obtained product is crystallized or converted to a mineral salt thereof and the salt is purified.

The preparation of the compounds of the general Formula I is described in more details in the followings.

A compound of the Formula II is suspended or dis solved in an aromatic or halogenated aliphatic solvent preferably in benzene or dichloromethanewith vigorous stirring, and an alkali hydroxide solutionpreferably sodium hydroxide solutionis added to the solution or suspension. The mixture is cooled to 0 to 5 C., and an u-halo-carboxylic halide, preferably chloroacetylchloride is added dropwise to the alkaline mixture with vigorous stirring. After several hours of stirring, the organic phase is separated, washed thoroughly with water, dried, evaporated, and the obtained l7-aza-20-oxo-2l-halosteroid derivative is recrystallized if necessary.

The compounds of the general Formula I wherein X is a halogen atom, obtained in the above step, are optionally subjected to substitution reactions.

The compounds of the general Formula I wherein X represents hydroxy or acyloxy group can be prepared as follows: a l7-aza-20-oxo-2 l-halo-steroid derivative is dissolved in an aliphatic ketonepreferably in acetoneand reacted with an alkali metal carboxylatepreferably with potassium carboxylate-at the boiling point of the mixture. The ester derivatives formed in the above reaction can be hydrolyzed to the corresponding derivatives containing free alcoholic hydroxy group, and these latter compounds can be reacted with carboxylic anhydrides or carboxylic halides to form other esters, e.g. esters formed with higher acids.

The compounds of the Formula I, wherein X represents a secondary or tertiary amino group are prepared as follows: the starting 17-aza-20-oxo-2l-halo-steroid derivative is dissolved in an inert solvent (e.g. in an alcohol, ketone, nitrile'or ether, preferably in acetone, ethanol, acetonitrile or tetrahydrofurane), and is reacted with an amine, e.g. with dimethylarnine, piperidine, triethylamine, pyridine or N-methylpyperazine at room temperature or at the boiling point of the solvent, depending on the nature of the amine reagent. If the end-product separates from the solution, the product is isolated by filtration, while in those cases in which it remains dissolved, the solution is evaporated, the residue is triturated with water, th product is filtered off, dried and crystallized if necessary. The obtained 2l-(secondary or tertiary amino)-20-oxo-l7-azasteroids can be converted into their salts according to known techniques.

The invention is elucidated in detail in the following examples. The examples are given for the purpose of illustration and not by Way of limitation.

EXAMPLE 1 3-ethylenedioxy-20-oxo-2l-chloro-l7-aza-5u-androstane 22.5 g. of 3-ethylenedioxy-l7-aza-5a-androstane are suspended in 1350 ml. of dichloromethane and 2200 ml. of sodium hydroxide solution are added to the suspension under vigorous stirring. The suspension is cooled to 0 C., and ml. of chloroacetyl chloride are added dropwise to the suspension within about minutes. The mixture is stirred at 0 C. for about additional 30 minutes, thereafter the organic phase is separated and the aqueous layer is extracted with 2 X 300 ml. of chloroform. The combined organic layers are washed successively with 2 N hydrochloric acid, 3% aqueous sodium hydrocarbonate solution and finally with water. The solution is dried and the solvent is distilled off.

The product is suspended in methanol at 0 C., filtered and dried. 23.5 g. (84%) of 3-ethylene-dioxy-20-oxo-21- chloro-l7-aza-5u-androstane are obtained, M.P.: 212- 215 C.

Analysis.Ca1cd. (percent): C, 66.72; H, 8.65; N, 3.53. Found (percent): C, 66.50; H, 8.78; N, 3,64.

EXAMPLE 2 3,20-dioxo21-chloro-17-aza-5a-androstane g. of 3-ethylenedioxy-2-oxo-21-chloro-17-aza-5a-androstane (prepared as in Example 1) are dissolved in 1000 ml. of peroxide-free tetrahydrofurane and 30 ml. of concentrated hydrochloric acid and 30 ml. of water are added. The solution is left stand for 24 hours at room temperature, thereafter it is adjusted to pH=7. The tetrahydrofurane is distilled off, about 300 ml. of water are added to the residue, the separated precipitate is filtered 01f, washed thoroughly with water and dried. 8.5 g. (86%) of 3,20-dioxo-21-chloro-17-aza5a-androstane are obtained, M.P.: 193-195 C. (recrystallized from a mixture of benzene and hexane).

Analysis.-Calcd. (percent): C, 68.33; H, 8.60; N, 3.98; C1, 10.07. Found (percent): C, 68.15; H, 8.48; N, 3.88; Cl, 9.88.

EXAMPLE 3 3,20-dioxo-2l-hydroxy-17-aza-5 u-androstane-21-acetate 5 g. of 3,20-dioxo-21-chloro-17-aza-5a-androstane are dissolved in 900 ml. of acetone, thereafter 2 g. of lithiumiodide ahd 14.3 g. of potassium acetate dissolved in 104 ml. of water are added to the solution. The reaction mixture is boiled for 9 hours under nitrogen atmosphere and vigorous stirring. Thereafter about 80 percent of the solvent is distilled off the residue is diluted with water, and the separated precipitate is filtered off, washed with water and dried. 5 g. (93%) of 3,20-dioxo-2l-hydroxy-17-aza- 5a-androstane-21-acetate are obtained, M.P.: 186189 C. (recrystallized from aqueous methanol).

Analysis.Calcd. (percent): C, 70.37; H, 8.86; N, 3.73. Found (percent): C, 70.60; H, 9.05; N, 3.86.

EXAMPLE 4 3,20-dioxo-2l-hydroxy-l7-aza-5a-androstane 14 g. of 3,20-dioxo-21-hydroxy-17-aza-5 u-androstane- 17-acetate (preared as in Example 3) are dissolved in 650 ml. of methanol, and 30.3 ml. of a 21% sodium methoxide solution are added. The mixture is stirred for 2 hours at room temperature under nitrogen atmosphere. Thereafter the mixture is adjusted to pH=7, and methanol is distilled off. The residue is diluted with water, the separated precipitate is filtered off, washed with water and dried. 12 g. (96%) of 3,20-dioxo-21-hydroxy-17-aza-5 a-androstane are obtained, M.P.: 210-211 C. (recrystallized from isopropanol).

Analysis.-Calcd. (percent): C, 72.03; H, 9.37; N, 4.20. Found (percent): C, 71.87; H, 9.36; N, 4.25.

EXAMPLE 5 3,20-dioxo-21-hydroxy-17-aza-5aandrostane-2l-hemisuccinate 5 g. of 3,20-dioxo-21-hydroxy-l7-aza-5u-androstane (prepared as in Example 4) are dissolved in 80 ml. of anhydrous pyridine and 5 g. of succinic anhydride are added to the solution. The mixture is left standing at room temperature for 48 hours, thereafter it is poured into ice water. The pH of the solution is adjusted to 2.5 to 3.0, the separated precipitate is filtered off, Washed with water and dried. 6 g. (93%) of 3,20-dioxo-21-hydroxy- 17-aza-5a-androstane-2l-hemisuccinate are obtained, M.P.: ZZZ-223 C. (boiled in acetone).

Analysis.Calcd. (percent): C, 66.49; H, 8.19; N, 3.23. Found (percent): C, 66.53 ;H, 8.27; N, 3.35.

6 EXAMPLE 6 3,20-dioxo-21-hydroxy-17-aza-5 u-androstane- ZI-hemisuccinate sodium salt 1.04 g. of 3,20-dioxo-21-hydroxy-17-aza-5a-androstane- 2l-hemisuccinate are dissolved in 60 ml. of ethanol, and 0.197 g. of sodium bicarbonate dissolved in 30 ml. of water are added to the solution under vigorous stirring. The solution is evaporated to dryness in vacuo at a temperature not exceeding 30 C. The residue is washed with anhydrous ethanol and ester. 1 g. (91%) of 3,20-dioxo- 2l-hydroxy-17-aza-5a-androstane-2l-hemisuccinate sodium salt are obtained.

Analysis.-Calcd. (percent): C, 63.27; H, 7.52. Found (percent): C, 63.12; H, 7.59.

EXAMPLE 7 3B-hydroxy-20-oxo-2l-chloro-17-aza-5a-androstane 3 g. of 3fi-hydroxy-17-aza-5a-androstane are reacted as described in Example 1. 3 g. of 3fi-hydroxy-20-oxo-21- chloro-17-aza-5u-androstane are obtained, M.P.: 220- 222 C. Yield: 79%.

Analysis.Calcd. (percent): C, 67.87; H, 9.11; N, 3.96; CI, 10.00. Found (percent): C, 67.75; H, 9.20; N, 4.05; CI, 9.85.

EXAMPLE 8 313,2l-dihydroxy-ZO-oxo-17-aza-5a-androstane-2l-acetate 6.5 g. of 3 8-hydroxy-20-oxo-2l-chloro-17-aza-5u-androstane are reacted as described in Example 3. 6 g. (93%) of 3fl,21-dihydroxy-20-oxo17-aza-5a-androstane- 21-acetate are obtained, M.P.: 183-184 C. (recrystallized from a mixture of isopropanol and hexane).

Analysis.-Calcd. (percent): C, 69.99; H, 9.35; N, 3.71. Found (percent): C, 69.80; H, 9.40; N, 3.80.

EXAMPLE 9 3,21-dihydroxy-20-oxo-17-aza-5u-androstane 3.7 g. of 3,21-dihydroxy-20-oxo-17-aza-5wandrostane- 21-acetate are reacted as described in Example 4. 3 g. (91%.), of 3,21-dihydroxy-20-oxo-17-aza-5a-androstane are obtained, M.P.: 227-229 C. (recrystallized from methanol).

Analysis.-Ca1cd. (percent): C, 71.60; H, 9.92; N, 4.18. Found (percent): C, 71.42; H, 9.99; N, 4.25.

EXAMPLE 10 3,20-dioxo-21-hydroxy-17-aza-5ozandrostane-Zl-methane-sulfonate 1 g. of 21-hydroxy-3,20-dioxo-17-aza-5a-androstane are dissolved in 70 ml. of pyridine. The solution is cooled to 0 C. and 2.6 ml. of methanesulfonic acid chloride are added to the solution within about 15 minutes under vigorous stirring. The reaction mixture is stirred for 3 hours at 0 C., thereafter it is dropped into cold (2 to 5 C.) water. The separated precipitate is filtered oif, washed successively with 5% hydrochloric acid and water and dried. 1 g. (81%) of 3,20-dioxo-21-hydroxy-17-aza-5a-androstane-Zl-methanesulfonate are obtained, M.P.: 146148 C. (recrystallized from methanol).

Analysis.-Calcd. (percent): C, 61.36; H, 8.09; N, 3.41; S, 7.80. Found (percent): C, 61.25; H, 8.18; N, 3.46; S, 7.71.

EXAMPLE 11 17-aza-17-N-(a-chloroacetyl)-estra-1,3,5(10)- triene-3-methylether 9.3 g. of 17-aza-estra-1,3,5(10)-triene-3-methylether are reacted as described in Example 1. 9.3 g. (78%) of 17-aza-17-N-(a-chloroacety1) estra 1,3,5 10)-triene-3- methylether are obtained, M.P.: 197-198 C.

Analysis.-Ca1cd. (percent): C, 69.05; H, 7.53; N, 4.03. Found (percent): C, 69.15; H, 7.40; N, 4.12.

7 EXAMPLE 12 2 l-pyridinium-ZO-oxo-17-aza-estra- 1,3,5 10) triene-3-methylether iodide 21-triethylammonium-20-oxo-17-aza-estra-1,3 ,5 l) triene-3-methylether-iodide 1 g. of 21 chloro 20 oxo-17-aza-estra-1,3,5(10)-triene-S-methylether are dissolved in 280 ml. of acetone and 1.3 g. of lithiumiodide and 2.5 ml. of triethylamine are added to the solution. The reaction mixture is boiled for 4 hours under nitrogen atmosphere. The separated substance is filtered oif, washed with acetone and dried. 1.3 g. (86%) of 21 triethylammonium 20 oxo-17-aza-estra- 1,3,5(1*0)-triene 3 methylether iodide are obtained, M.P.: 214-216 C. (recrystallized from ethanol).

Analysis.-Calcd. (percent): C, 57.77; H, 7.65; N, 5.18; I, 23.47. Found (percent): C, 57.77; H, 7.80; N, 5.23; I, 23.47.

EXAMPLE 14 21-iodo-20-oxo-17-aza-estra-l ,3,5 )-triene-3- methylether 3 g. of 21 chloro 20 oxo 17-aza-estra 1,3,5(10)- triene-3-methylether are dissolved in 600 ml. of acetone and 4 g. of sodium iodide are added to the solution. The reaction mixture is boiled for 30 minutes under nitrogen atmosphere, the separated sodium chloride is filtered oil and the filtrate is evaporated in vacuo. The residue is suspended in water, the separated 21 iodo 20-oxo-17-azaestra-1,3,5(10)-triene 3 methylether is filtered off and dried. 3.7 g. (97.5%) of the product are obtained, M.P.: 180-182 C.

Analysis.-Calcd. (percent): C, 54.68; H, 5.89; N, 3.15; I, 28.55. Found (percent): C, 54.50; H, 5.99; N,

EXAMPLE 2l-hydroxy-20-oxo-17-aza-estra-1,3,5 10) -triene-3- methylether-Zl-acetate 7.7 g. of 21 chloro 20-oxo-17-aza-estra-1,3,5(10)- triene-3-methylether are reacted as described in Example 3. 8 g. (94%) of 21 hydroxy oxo-17-aza-estra- 1,3,5(10) triene 3 methylether-Zl-acetate are obtained, M.P.: 172-174 C. (recrystallized from methanol).

AnaIysz's.--Calcd. (percent): C, 71.14; H, 7.87; N, 3.77. Found (percent): C, 71.18; H, 7.95; N, 3.85.

EXAMPLE 16 2l-N-(N'-methylpiperaz.inyl)-20-oxo-l7-aza-estra- 1,3 ,5 1 0 -triene-3-methylether separated precipitate is filtered off, washed thoroughly with water and dried. The obtained steroid base, melting at 155-157 C. is dissolved in ethanol and the corresponding dihydrochloride is precipitated with ethanolic hydrochloric acid. The product is recrystallized item a mixture of methanol and acetone. 1.3 g. (93%) of 21-N-(N methylpiperazinyl)-20-oxo-17-aza-estra 1,2,3,5(10) triens-3-methylether-dihydroch1oride are obtained, M.P.: 170172 C.

Analysis.Calcd. (percent): C, 72.93; H, 9.06; N, 10.21. Found (percent): C, 73.00; H, 9.00; N, 10.25.

EXAMPLE 17 3-ethylenedioxy-20-oxo-21-N-(N-methylpiperazynil)- 17-aza-5a-androstane 0.88 g. of 21 chloro 20 oxo 17 aza-5a-androstane-3-ethyleneketal are reacted as described in Example 16. 1 g. (97%) of 3 ethylenedioxy 20-oxo-21-N-(N'- methylpiperazinyl)-17-aza 5a androstane-dihydrochloride are obtained, M.P.: 242-244 C. (recrystallized from methanol).

Analysis.-Calcd. (percent): C, 70.56; H, 9.86; N, 9.14. Found (percent): C, 70.40; H, 9.86; N, 9.25.

EXAMPLE 18 21-(N'-methylpiperazino)-20-oxo-17-aza-estra- 1,3 ,5 10) -triene-3-methylether 2 g. of 21 chloro 20 17-aza-estra-1,3,5(l0) -triene- 3-methylether are dissolved in a mixture of 150 ml. of benzene and 170 ml. of acetonitrile, and 6 g. of N-methylpiperazine are added. The reaction mixture is maintained at 70 C. for 6.5 hours, the solvent is distilled off, the residue is triturated with water, the separated substance is filtered ofi, washed thoroughly with water and dried. The obtained steroid base melting at 155157 C. is dissolved in ethanol and reacted with ethanolic hydrochloric acid. The separated substance is crystallized from a mixture of methanol and acetone. 2.2 g. (78%) of 21-(N'- methylpiperazino) 20 oxo 17 aza estra-1,3,5(l0)- triene 3 methylether dihydrochloride are obtained. M.P.: 169-171 C.

Analysis.Calcd. (percent): C, 72.93; H, 9.06; N, 10.21. Found (percent): C, 72.58; H, 8.91; N, 10.00.

What we claim is:

1. A compound having the formula:

CHzOX crno wherein X is hydroxyl, chloro, acetate, pyridino, triethylamino, or N -methylpiperazinyl, or the iodide salt thereof.

2. The compound defined in claim 1 and consisting of 21 chloro-ZO-oxo-17-aza-estra-1,3,5(10) triene 3 methylether.

(References on following page) I 9 10 References Cited V. Nelson et al., Chem. Abstr., v01. 76, col. 99925j, US. Pat. 3,634,419. UNITED STATES PATENTS Tuba et a1., Chem. Abstn, V01. 76, col. 99920d 1972 3,153,645 10/1964 Ayer 260-268 PC Abstracting German 2,130,282. 3,180,864 4/1965 Wendt 260268 PL Tuba 61131.,(3116111. Abstr.,v0l. 76, CO1. 99132d 1972 3,523,942 8/1970 Holden 260239.8 5 Abstracting German 2, 130, 323. 3 6 4,419 1 1 72 N1 260-326. B

3 9 6 son 5 DONALD G. DAUS, Prlmary Exammer OTHER REFERENCES Gut et 3]., Chem. Abstn, vol. 60, col. 12078d (1964).

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